Acute lung injury (ALI) is a common, often lethal, complication in the critically ill. We have made the novel observation that febrile range hyperthermia (FRH) exacerbates ALI by greatly increasing recruitment of neutrophils (PMNs) to the lung. By measuring trans-alveolar PMN recruitment in response to intratracheal IL-8, we demonstrated that exposing mice to FRH for 16-24 h increased subsequent IL-8-directed trans-alveolar PMN recruitment 10-23-fold. The priming effect of FRH lasted for >48h and was blocked by inhibitors of ERK and p38. Using a novel adoptive PMN transfer technique, we showed that FRH likely exerts priming effects on both PMNs and the pulmonary vasculature. Our preliminary results demonstrate that exposing mice to FRH increases mRNA levels for some of these molecules in lung (junctional adhesion molecule-A) and circulating leukocytes (CD18). HYPOTHESIS: We propose that FRH modifies endothelium and PMNs to increase CAPACITY for TEM. We postulate a central role for p38 and ERK, regulation of critical adhesion molecule expression, and modification of endothelial and PMN cytoskeleton. SPECIFIC AIMS: The overall objective of these studies is to understand the mechanisms by which FRH augments PMN-dependent ALI. In aim 1, we will use our in vivo trans-alveolar PMN recruitment model to fill in gaps in our understanding of the process. In aims 2 and 3, we will use in vitro and in vivo models to define the molecular events in endothelium and PMNs through which FRH increases CAPACITY for trans-alveolar PMN recruitment, focusing on p38- and ERK-dependent gene activation. RELEVANCE: Antipyresis is difficult to achieve in the critically ill and exertional/environmental hyperthermia is often unavoidable. Ablating fever may eliminate its beneficial as well as its harmful effects. A better understanding of its molecular mechanisms will allow us to selectively block the harmful effects of fever/hyperthermia and exploit the beneficial effects. PUBLIC HEALTH RELEVANCE. Exposure to elevated body temperatures as occurs during fever or heat stroke changes the blood vessels and white blood cells to increase movement of white blood cells from the blood to the lung. During infections this effect can help eliminate bacteria, but it can also cause severe lung injury. Since blocking fever may eliminate its beneficial as well as its harmful effects, a better understanding of how high temperatures cause these changes will allow us to selectively block the harmful effects of fever. The same knowledge will help us develop better therapies to prevent the complications of heat stroke, a growing global health problem.